A defective fibrinolytic system participates in the persistence of venous and arterial thrombi. The two principal inhibitors of fibrinolysis are plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), and α2-antiplasmin, a specific plasmin inhibitor. Regulation of the plasmin system by PAI-1 regulates both fibrinolysis in the vasculature as well as extracellular matrix (ECM) degradation in the tissues. PAI-1, a 50-kDa glycoprotein, belongs to the serine proteinase inhibitor (serpin) superfamily. In its active form, PAI-1 controls tPA and uPA activity through the rapid formation of an inactive complex. The active form is unstable and converts spontaneously into a non-inhibitory latent form. In plasma, PAI-1 is stabilized through binding with vitronectin. A third conformation, the non-inhibitory substrate form, interacts with tPA and uPA resulting in the cleavage and irreversible inactivation of PAI-1 and the regeneration of the proteinase activity.
Abnormal variations in PAI-1 plasma levels have been correlated with a disturbed balance in the fibrinolytic process. Patients with decreased PAI-1 plasma levels suffer from abnormal bleeding tendencies while increased plasma PAI-1 concentrations are positively correlated with several cardiovascular diseases, including venous thromboembolism, sepsis and coronary artery disease. Elevated PAI-1 plasma concentrations are correlated with the insulin-resistance syndrome and increased local expression of PAI-1 is observed in atherosclerotic plaques.